Department of Anesthesiology, Leiden University Medical Center, The Netherlands.
Curr Pharm Des. 2012;18(37):5994-6004. doi: 10.2174/138161212803582469.
Opioids induce respiratory depression via activation of μ-opioid receptors at specific sites in the central nervous system including the pre-Bötzinger complex, a respiratory rhythm generating area in the pons. Full opioid agonists like morphine and fentanyl affect breathing with onset and offset profiles that are primarily determined by opioid transfer to the receptor site, while the effects of partial opioid agonists such as buprenorphine are governed by transfer to the receptor site together with receptor kinetics, in particular dissociation kinetics. Opioid-induced respiratory depression is potentially fatal but may be reversed by the opioid receptor antagonist naloxone, an agent with a short elimination half-life (30 min). The rate-limiting factor in naloxone-reversal of opioid effect is the receptor kinetics of the opioid agonists that requires reversal. Agents with slow dissociation kinetics (buprenorphine) require a continuous naloxone infusion while agents with rapid kinetics (fentanyl) will show complete reversal upon a single naloxone dose. Since naloxone is non-selective and will reverse analgesia as well, efforts are focused on the development of compounds that reverse opioid-induced respiratory depression without affecting analgesic efficacy. Such agents include ampakines and serotonin agonists which are aimed at selectively enhancing central respiratory drive. A novel approach is aimed at the reduction of respiratory depression from opioid-activation of (micro-)glia cells in the pons and brainstem using micro-glia cell stabilizers. Since this approach simultaneously enhances opioid analgesic efficacy it seems an attractive alternative to the classical reversal strategies with naloxone.
阿片类药物通过在中枢神经系统的特定部位（包括前脑桥呼吸节律生成区）激活 μ-阿片受体而导致呼吸抑制。像吗啡和芬太尼这样的完全阿片类激动剂通过与受体结合的转移来主要决定其呼吸开始和结束的特征，而部分阿片类激动剂（如丁丙诺啡）的作用则受与受体结合以及受体动力学（特别是解离动力学）的控制。阿片类药物引起的呼吸抑制可能是致命的，但可以被阿片受体拮抗剂纳洛酮逆转，纳洛酮的消除半衰期（30 分钟）较短。纳洛酮逆转阿片类药物作用的限速因素是需要逆转的阿片类激动剂的受体动力学。解离动力学较慢的药物（丁丙诺啡）需要持续输注纳洛酮，而解离动力学较快的药物（芬太尼）在单次给予纳洛酮后就会完全逆转。由于纳洛酮是非选择性的，也会逆转镇痛作用，因此人们致力于开发既能逆转阿片类药物引起的呼吸抑制又不影响镇痛效果的化合物。这些药物包括 AMPAkines 和 5-羟色胺激动剂，它们旨在选择性地增强中枢呼吸驱动。一种新方法旨在通过使用小胶质细胞稳定剂减少阿片类药物激活脑桥和延髓中小胶质细胞引起的呼吸抑制。由于这种方法同时增强了阿片类药物的镇痛效果，因此它似乎是一种有吸引力的替代纳洛酮经典逆转策略的方法。
